Cystic fibrosis (CF) is a common autosomal-recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a regulated Cl- channel. Mutations in the CFTR gene cause a loss of function of the CFTR Cl- channel and thus contribute to the hallmark of the disease: defective electrolyte transport by affected epithelia. Despite standard therapy for the symptoms of CF lung disease, CF is a lethal disease. Our data suggest that adenovirus may be a good vector for expressing CFTR in airway epithelia and correcting the electrolyte transport abnormalities. Our safety data are also encouraging. Thus, given the lethal nature of the disease, the realization that gene transfer would represent a major advance in treatment, and the encouraging preliminary studies, we propose to test the biochemical efficacy, clinical efficacy, and safety of adenovirus vectors for transfer of CFTR cDNA to humans. The data from these studies should define important variables for treatment, should identify potential problems associated with vector administration, and should guide vector development. Thus, they will directly impact the future direction of gene transfer to treat CF. 1. Adenovirus-mediated gene transfer to the nasal epithelium. In this study, we propose to administer adenovirus to the nasal epithelium in order to assess safety and biochemical efficacy (the ability to correct the Cl- channel defect). 2. Repeat administration of an adenoviral vector to nasal administration. We will test whether repeat administration of vector produces biochemical efficacy and whether it will cause an inflammatory or immune response that could limit efficacy or be harmful to the patient. These studies will also assess the duration of expression and the required dose of vector. 3. Assessment of clinical efficacy of adenovirus-directed CFTR expression in the maxillary sinus epithelium. To determine whether delivery of CFTR will have clinical efficacy, we will examine its effect on CF maxillary sinus disease. The maxillary sinuses, are universally involved in CF, with physiologic abnormalities and a pathophysiology similar to that of the lower airways. The results will also assess the issue of whether it is necessary to treat the submucosal glands to achieve clinical efficacy. 4. Repeat administration of adenovirus to intrapulmonary airway epithelium. With the knowledge obtained from the first three studies, we will administer adenoviral vector to the lung. Our goals will be to assess biochemical efficacy, clinical efficacy, and safety.